Papillary thyroid carcinoma (PTC) is a relatively benign neoplasia, with occult lesions found in up to 10% of the general population at time of autopsy. We propose that this is attributable to the RET/PTC oncogenes that not only increase proliferation and viability, but also drive an autoreactive anti-tumor response. Indeed, RET/PTC-driven PTC and Hashimoto's thyroiditis (HT) are strongly coincidental and individuals who present with both conditions have a better prognosis than patients with malignant undifferentiated thyroid carcinomas without features of autoimmunity. Our established and preliminary studies focused upon one of the most common RET/PTC proteins, RET/PTC3 (RP3), point to a potential mechanistic basis: First, RP3 itself can provide antigenicity (signal 1) via the breakpoint region, aberrant autophosphorylation and phosphorylation of downstream targets, and possibly through conformational effects that modulate antigen processing. Second, RP3 has been shown to induce a wide array of potent inflammatory mediators (signal 2), thereby providing the co-stimulation required for an effective adaptive response. This scenario provides contrast to the popular notion that inflammation encourages the development and spread of cancer. Using a combination of biochemical, in vitro and in vivo approaches, we will explore these activities and their impact on the evolution of PTC in two specific aims executed mainly in parallel over the two year period. These studies will set the stage for the development of transgenic models that allow for more powerful dissection of the interplay between cancer and the host defense system. In addition, they may point to general strategies for enhancing cancer immunotherapy. PUBLIC HEALTH RELEVANCE: For over a century scientists and clinicians have tried to harness the specificity and lethality of the immune system to battle cancer. This has been difficult because, unlike infections by bacteria and viruses, cancers are much harder for the immune system to recognize. An exception to this generality may be thyroid cancers that are caused by an oncogene termed RP3. In this case, immune responses to the cancer are relatively robust. Our plan is to explore the basis for this heightened recognition, with the hope of applying what we learn to cancers that are less visible to the immune system.